ES2463717T3 - Compounds, formulations, and methods to reduce wrinkles, folds and sagging skin - Google Patents

Abstract

A composition comprising at least one active ingredient selected from an a2 adrenergic receptor agonist, a pharmaceutically acceptable salt thereof and a combination thereof for use in the therapeutic reduction of wrinkles, folds or sagging skin, wherein the A2 adrenergic receptor agonist is selected from the group consisting of brimonidine, tetrahydrozalin, oxymetazoline, and xylometazoline, and wherein said composition is to be administered topically for sagging, folds, and / or wrinkles of the skin of a person in need Treatment in an effective amount to improve wrinkles, folds or sagging skin.

Description

Compounds, formulations, and methods to reduce wrinkles, folds and sagging skin

5 The present teachings are directed to compounds and methods for the treatment or prevention of wrinkles and sagging skin.

BACKGROUND OF THE INVENTION

10 Wrinkles, folds and sagging skin are common and generally undesirable. Such skin conditions can be the result of many causes, such as aging.

Many different treatments are used to reverse wrinkles, folds or sagging skin. Examples of these treatments include the injection of toxins such as botulinum toxin; filler injection such as collagen, fat, and

15 hyaluronic acid, topical formulations of tretinoin, chemical peeling, dermabrasion, laser rejuvenation, microdermabrasion, photorejuvenation, and plastic surgery such as face lift and face lift. All these procedures have associated side effects and / or precautions (see, for example, the website http://www.mayoclinic.com/health/wrinkle-treatment/SN00008)

20 Thus, there remains a need for compositions and methods to reduce wrinkles, folds and sagging skin.

SUMMARY OF THE INVENTION

The present inventors have developed topical skin formulations and methods to reduce wrinkles, folds and

25 sagging skin. The compositions of the invention comprise defined a2 adrenergic receptor agonists, which have a skin tension effect and improve skin wrinkles, skin folds, sagging skin or all. These compounds can be administered in topical skin compositions that promote the effectiveness of the compound in amounts effective to improve wrinkles, folds and sagging skin without inducing intolerable side effects, which include systemic side effects.

30 Consequently, in several aspects, the present teachings describe methods to reduce wrinkles, folds and sagging skin. In various configurations, these methods comprise topically administering to the skin of a person such as a patient in need of treatment a composition comprising an active ingredient selected from at least one defined a2 adrenergic receptor agonist, a pharmaceutically acceptable salt thereof. Y

35 a combination thereof.

In several aspects, a composition is administered in an amount effective to improve wrinkles, folds and sagging skin. An effective amount to improve wrinkles, folds and sagging skin is any amount that is locally effective to improve wrinkles, folds and sagging skin after topical administration.

40 A special skin preparation is not required before administration of a composition, although cleansing the skin before administration can improve effectiveness. Additionally, several formulations may be non-restrictive with respect to other skin care and cosmetic products. The application of a formulation comprising an a2 adrenergic receptor agonist may be compatible with, for example, separate application of makeup.

In addition, in some configurations, a cosmetic or skin care product may comprise an a2 adrenergic receptor agonist, so that the user can simultaneously receive, for example, the benefits of the effects of skin tension and effects of masking by application of a single product to the skin.

50 The a2 adrenergic receptor agonist is selected from brimonidine, tetrahydrozalin, oxymetazoline, and xylometazoline. In some embodiments, an a2 adrenergic receptor agonist may be a reversible a2 adrenergic receptor agonist.

In several embodiments, a composition of the present teachings comprising an a2 adrenergic receptor agonist may further comprise a pharmaceutically acceptable carrier. In some aspects, a composition can be

55 an atomization, a mist, an aerosol, a lotion, a foam, a gel, a cream, an ointment, a paste, an ointment, an emulsion, a liposomal suspension, a colloid or a combination of these, while in others aspects, a composition can be formulated as a cosmetic, a makeup base, a moisturizer, a sunscreen agent.

In some configurations, a composition may further comprise a pharmaceutically acceptable carrier, which may comprise an aqueous gel comprising water and a gelling amount in water of a gelling agent.

pharmaceutically acceptable selected from a carbomer, a glycerol polyacrylate, and a mixture of these, and can be an atomization, a mist, an aerosol, a lotion, a foam, a gel, a cream, an ointment, a paste, an ointment , an emulsion, a liposomal suspension, a colloid or a combination of these. A cream or ointment may comprise stearic acid, stearyl alcohol, cetyl alcohol, glycerin, and / or water.

In several configurations, a topical composition may comprise the a2 adrenergic receptor agonist, a pharmaceutically acceptable salt or a combination thereof in an amount of at least about 0.01% w / w to about 5% w / w, and in addition, a composition it can have a pH of about 5 to about 8. In several aspects, the compositions of the present teachings may further comprise a preservative, a local anesthetic, and / or a skin moisturizer.

In some embodiments, a topical composition for reducing wrinkles, folds and / or sagging skin, hereinafter referred to as "skin tightening," may comprise at least a first active ingredient selected from the defined a2 adrenergic receptor agonist , a pharmaceutically acceptable salt thereof and a combination thereof, and at least a second pharmaceutically active ingredient selected from azelaic acid, benzoyl peroxide, isotretinoin, an antibiotic, a chemically modified antibiotic, a pharmaceutically acceptable salt thereof and a combination. thereof. In some configurations, an antibiotic may be clindamycin, doxycycline, erythromycin, metronidazole, sulfacetamide, tetracycline, or a combination of these. A topical composition may comprise the first active ingredient in a concentration as prescribed or in an over-the-counter concentration. In some configurations of the methods of the present teachings, a chemically modified antibiotic or antibiotic can be administered in an amount effective for the treatment of sagging, folds and / or wrinkles of the skin.

Symptoms that can be improved include symptoms such as, for example, skin wrinkles, skin folds and sagging skin.

In various aspects of the present teachings, an amount of an effective skin tightening composition may be an amount that begins to provide the effects of skin tightening within approximately 5 minutes after administration. In several other aspects, an effective amount for skin tightening can be an amount that reduces wrinkles, folds or sagging skin for at least about 8 hours, for up to about 12 hours, for up to about 18 hours, or for Up to about 24 hours.

In certain aspects of the present teachings, the present inventors have developed pharmaceutical packages to improve wrinkles, folds or sagging skin. A package according to these aspects may comprise a first active ingredient selected from at least one defined a2 adrenergic receptor agonist, a pharmaceutically acceptable salt thereof and a combination thereof, in an amount effective to improve wrinkles, folds or sagging of the skin. A package may have a second pharmaceutically active ingredient selected from azelaic acid, benzoyl peroxide, isotretinoin, an antibiotic, a chemically modified antibiotic, a pharmaceutically acceptable salt thereof and a combination thereof, and may also comprise a pharmaceutically acceptable carrier, a container, and instructions for the use of the topical composition.

In some configurations, methods to reduce wrinkles, folds or sagging skin may comprise selecting a first active ingredient based on whether it has agonist activity of the a2 adrenergic receptor, and topically administering to the skin of an individual such as a patient in need of treatment a composition comprising an active ingredient selected from at least one a2-defined adrenergic receptor agonist, a pharmaceutically acceptable salt thereof and a combination thereof, in an amount effective to reduce wrinkles, folds or sagging of the skin. In other configurations, the methods to reduce wrinkles, folds or sagging skin may comprise selecting the active ingredient on the basis that it has wrinkle enhancement activity, folds

or sagging skin, or on the basis that it has activity of the agonist of the adrenergic receptor a2 and activity of improvement of wrinkles, folds or sagging skin.

DETAILED DESCRIPTION

The present inventors have discovered compounds, compositions, formulations, and methods to reduce wrinkles, folds or sagging skin. The methods comprise topically administering to the skin a composition or formulation comprising an a2defined adrenergic receptor agonist.

The a2 adrenergic receptor agonists of the present teachings are listed in Table 1 below.

TABLE 1

(5-Bromo-quinoxalin-6-yl) - (4,5-dihydro-1H-imidazol-2-yl) -amine (Brimonidine)

Tetrahydrozalin

Oxymetazoline

Xylometazoline

The compounds of the present compositions and which are used in the present methods are well known in the art as a2 adrenergic receptor agonists, and have potent vasoconstrictor effects when introduced into the body.

5 of mammals, particularly humans. The compounds according to the teachings of the present invention may further include pharmaceutically acceptable salts of the compounds described herein, analogs thereof, prodrugs thereof and combinations thereof.

The compounds of the present teachings can be prepared according to synthetic procedures either

10 known, for example, using the general synthesis procedures set forth in US Pat. no. 3,890,319 (issued June 17, 1975) and U.S. Pat. no. 4,029,792 (granted on June 14, 1977) which are hereby incorporated herein by reference. Scheme 1 below illustrates a method for synthesizing the compounds of Formula I

Scheme 1

The compounds of the invention can be synthesized by the reaction of suitable quinoxalines 15 with thiophosgene 5 20 to form the corresponding isothiocyanates 25. The reaction with thiophosgene can be carried out in aqueous solution.

or in aqueous hydrochloric acid diluted at room temperature over a period of approximately 2 hours. Alternatively, the thiophosgene 20 dissolved in a water immiscible solvent, such as chloroform, can be added to a basic aqueous solution (sodium carbonate) of quinoxalines 15 and stirred for approximately two hours. In the first alternative, the isothiocyanates 25 precipitate from the reaction mixture. Precipitation can be completed by neutralization with excess of

10 aqueous base. The precipitated isothiocyanates can be recovered by filtration and dissolved in a suitable solvent, for example, chloroform, to form a solution. The solution can be dried (for example, over MgSO4), filtered, and concentrated to produce isothiocyanates.

Isothiocyanates 25 can be treated with an excess of appropriately substituted ethylene diamine to form the 3

Corresponding quinoxalin-6-yl-thioureas 35. Isothiocyanates 25 may react with an excess (for example, 5 moles to 1 mole) of ethylene diamine 30 in a suitable solvent, for example, diethyl ether, benzene, chloroform or dioxane . The reaction can be carried out at room temperature for approximately 2 hours. The 3-quinoxalin-6-yl-thioureas 35 precipitate and can be recovered by filtration and washing the filter cake with solvent.

The cyclization of 3-quinoxalin-6-yl-thioureas 35 to provide the compounds of the invention 10 can be carried out by heating a suspension of thioureas 35 with copper or mercury oxide in a suitable organic solvent, for example, ethanol. Copper oxide or mercury can be replaced by an organic soluble copper or mercury salt, for example, copper or mercury acetate. The reaction mixture can be filtered, to remove the byproduct of copper or mercury sulphide, and the filtrate can be concentrated to give the compounds 10 in a crude form. Compounds 10 can

Recrystallize as the free base or become an acid addition salt by conventional reaction with a suitable acid. In some cases, the cyclization can be affected by simple reflux of the thioureas in a suitable organic solvent, for example, methanol, in the absence of copper oxide or mercury.

Quinoxalines 15 can be synthesized by well-known synthesis procedures, for example, procedures

30 described in J. A. JOULE et al., HETEROCYCLIC CHEMISTRY 189-224 (3rd ed. 1995), hereby incorporated herein by reference.

Topical formulations of the invention

In certain aspects, the compounds of the present teachings can be administered to the affected area of the skin in a pharmaceutically acceptable topical carrier. As used herein, a pharmaceutically acceptable topical carrier can be any pharmaceutically acceptable formulation that can be applied to the skin surface for topical, dermal, intradermal, or transdermal administration of a pharmaceutical product or medicament. The combination of a pharmaceutically acceptable topical carrier and a compound of the invention is called a topical formulation of the invention. Topical formulations of the invention can be prepared by mixing a compound of the invention with a topical carrier according to methods known in the art, for example, methods provided by standard reference texts such as, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1577-1591, 1672-1673, 866885 (Alfonso R. Gennaro ed. 19.a ed. 1995); Ghosh, T. K .; and others TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS (1997), which are incorporated in this way in this description as a reference.

A topical carrier useful for topical administration of the compounds of the invention may be any carrier known in the art for topically administered pharmaceutical products, for example, but not limited to, pharmaceutically acceptable solvents, such as a polyol or water; emulsions (oil-in-water or water-in-oil emulsions), such as creams or lotions; micro emulsions; gels; ointments; liposomes; powder; and aqueous solutions or suspensions, such as standard ophthalmic preparations.

Emulsions, gels, and ointments as topical carriers

In some embodiments, a topical carrier used to deliver a compound of the invention may be an emulsion, gel, or ointment. Emulsions, such as creams and lotions, are suitable for topical formulations for use in the invention. An emulsion, as used herein, is defined as a dispersed system comprising at least two immiscible phases, one phase dispersed in others as droplets with a diameter of about 0.1 microns to about 100 microns. An emulsifying agent can be included to improve stability. When water is the dispersed phase and an oil is the dispersion medium, the emulsion is referred to as a water-in-oil emulsion. When an oil is dispersed as droplets through the aqueous phase as droplets, the emulsion is referred to as an oil-in-water emulsion. Emulsions, such as creams and lotions that can be used as topical carriers and their preparation are described in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 282-291 (Alfonso R. Gennaro ed. 19th ed. 1995), incorporated herein by the Present as a reference.

In another aspect, a topical carrier used to administer a compound of the invention may be a gel, for example, a two-phase gel or a one-phase gel. Gels are defined herein as semi-solid systems consisting of suspensions of small inorganic particles or large organic molecules interpenetrated by a liquid. When the gel mass comprises a network of small discrete inorganic particles, it is classified as a two-phase gel. Single phase gels consist of organic macromolecules evenly distributed through a liquid so that there are no apparent boundaries between the dispersed macromolecules and the liquid. The gels suitable for use in the invention are described in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1517-1518 (Alfonso R. Gennaro ed. 19 ed. 1995), incorporated herein by reference. Other suitable gels are described in US Pat. no. 6,387,383 (granted May 14, 2002); U.S. Patent no. 6,517,847 (granted on February 11, 2003); and U.S. Pat. no. 6,468,989 (granted October 22, 2002), each of which is hereby incorporated by reference.

Polymeric thickeners (gelling agents) that can be used include those known to those skilled in the art. Non-limiting examples of polymeric thickeners include hydrophilic and hydroalcoholic gelling agents frequently used in the pharmaceutical and cosmetic industries. Some non-limiting examples of hydrophilic and hydroalcoholic gelling agents include "CARBOPOL®" (BF Goodrich, Cleveland, Ohio), "HYPAN®" (Kingston Technologies, Dayton, NJ), "NATROSOL®" (Aqualon, Wilmington, Del.), "KLUCEL®" (Aqualon, Wilmington, Del.), Or "STABILEZE®" (ISP Technologies, Wayne, NJ). In some aspects, the gelling agent may comprise between about 0.2% to about 4% by weight of the composition, i.e. w / w. More particularly, the range of the percentage by weight of the composition for the "CARBOPOL®" may be between about 0.5% w / w to about 2% w / w, while the range of the weight percent for the "NATROLSOL®" and "KLUCEL®" can be between about 0.5% to about 4%. In various configurations, the range of the percentage by weight of the composition for "HYPAN®" and "STABILEZE®" may be between 0.5% w / w to about 4% w / w.

"CARBOPOL®" is one of numerous cross-linked acrylic acid polymers that are given the general adopted name of carbomer. These polymers dissolve in water and form a clear or slightly hazy gel after neutralization with a caustic material such as sodium hydroxide, potassium hydroxide, triethanolamine, or other amine bases. "KLUCEL®" is a cellulose polymer that disperses in water and forms a uniform gel after complete hydration. Other examples of

gelling polymers include hydroxyethyl cellulose, cellulose gum, crosslinked MVE / MA decadiene polymer, PVM / MA copolymer, or combinations thereof.

In another embodiment, a topical carrier used to administer may be an ointment. Ointments are defined in the present description as oil semi-solids that contain little or no water. An ointment may be based on hydrocarbon, such as a wax, petrolatum, or mineral gel oil. Ointments suitable for use in the invention are well known in the art and are described in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 15851591 (Alfonso R. Gennaro ed. 19th ed. 1995), hereby incorporated herein by reference. .

Topical aqueous formulations

In another embodiment, a topical carrier used in topical formulations may be an aqueous suspension or solution. Well-known ophthalmic suspensions and solutions may be suitable topical carriers. Examples of suitable aqueous topical formulations are described in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1563-1576 (Alfonso R. Gennaro ed. 19th ed. 1995), incorporated herein by reference. Other examples of aqueous optical carrier systems are described in US Pat. no. 5,424,078 (granted June 13, 1995); U.S. Patent no. 5,736,165 (granted on April 7, 1998); U.S. Patent no. 6,194,415 (granted on February 27, 2001); U.S. Patent no. 6,248,741 (granted June 19, 2001); U.S. Patent no. 6,465,464 (granted October 15, 2002), all of these patents are hereby incorporated herein by reference.

In several aspects, the pH of an aqueous topical formulation may be in the range of about 6 to about 8, or about 6.3 to about 6.5. To stabilize the pH an effective amount of a buffer can be included. In some embodiments, a buffering agent may be present in an aqueous topical formulation in an amount of about 0.05% w / w to about 1% w / w. Acids or bases can be used to adjust the pH as necessary. Non-limiting examples of buffering agents include acetate buffers, citrate buffers, phosphate buffers, lactic acid buffers, and borate buffers.

Tonicity adjusting agents can be included in the topical aqueous formulations of the present teachings. Examples of tonicity adjusting agents include, but are not limited to, sodium chloride, potassium chloride, mannitol, dextrose, glycerin, and propylene glycol. The amount of the tonicity agent can vary widely depending on the desired properties of the formulation. In one embodiment, the tonicity adjusting agent is present in the aqueous topical formulation in an amount of about 0.5% w / w to about 0.95% w / w.

In some aspects, aqueous topical formulations may have a viscosity in the range of about 15 cps to about 25 cps. The viscosity of the aqueous solutions of the invention can be adjusted by the addition of viscosity adjusting agents, for example, but not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, or hydroxyethyl cellulose.

In certain embodiments, an aqueous topical formulation may be an isotonic saline solution comprising a preservative, such as benzalkonium chloride or chlorine dioxide, a viscosity adjusting agent, such as polyvinyl alcohol, and a buffer system such as sodium citrate. and citric acid.

Excipients

Topical formulations of the present teachings may comprise pharmaceutically acceptable excipients such as those listed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 866-885 (Alfonso R. Gennaro ed. 19th ed. 1995; Ghosh, TK; and other transdermal AND TOPICAL DRUG DELIVERY SYSTEMS (1997), incorporated herein by reference, and may include, without limitation, protectors, adsorbents, demulcent, preservative emollients, antioxidants, moisturizers, buffering agents, solubilizing agents, skin penetrating agent, and surfactants.

Protectors and adsorbents include, but are not limited to, fine powders, zinc stearate, collodion, dimethicone, silicones, zinc carbonate, aloe vera gel and other aloe products, oil with vitamin E, allantoin, glycerin, petrolatum, and zinc oxide.

Suitable demulcents include, but are not limited to, benzoin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinyl alcohol.

Suitable emollients include, but are not limited to, animal and vegetable oils and fats, myristyl alcohol, alum, and aluminum acetate.

Suitable preservatives include, but are not limited to, quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimide, decualinium chloride, and cetylpyridinium chloride; mercurial agents, such as phenylmercury nitrate, phenylmercury acetate, and thimerosal; alcoholic agents, for example, chlorobutanol, ethyl phenylalcohol, and benzyl alcohol; antibacterial esters, for example, esters of parahydroxybenzoic acid; and other antimicrobial agents such as chlorhexidine, chlorocresol, benzoic acid and polymyxin.

Chlorine dioxide (ClO2), preferably stabilized chlorine dioxide, can be used as a preservative for use with the topical formulations of the invention. The term "stabilized chlorine dioxide" is well known in the industry and by those with experience in the art. The stabilized chlorine dioxide includes one or more chlorine dioxide precursors such as one or more complexes containing chlorine dioxide and / or one or more components containing chlorite and / or one or more other entities capable of decomposing or being decomposed in an aqueous medium to form chlorine dioxide. U.S. Pat. no. 5,424,078 (issued June 13, 1995), incorporated herein by reference, describes a form of stabilized chlorine dioxide and a method of producing it, which can be used as a preservative for aqueous ophthalmic solutions and is useful in the topical formulations of the invention. The making

or production of certain stabilized chlorine dioxide products is described in US Pat. no. 3,278,447, incorporated herein by reference. A commercially available stabilized chlorine dioxide that can be used in the practice of the present invention is the patented stabilized chlorine dioxide from BioCide International, Inc. of Norman, OK, sold under the trademark Purogene.TM. or Purite.TM. Other suitable stabilized chlorine dioxide products include those sold under the DuraKlor trademark by Rio Linda Chemical Company, Inc., and those sold under the Antheium Dioxide trademark by International Dioxide, Inc.

Suitable antioxidants include, but are not limited to, ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents such as EDTA and citric acid.

Suitable humectants include, but are not limited to, glycerin, sorbitol, polyethylene glycols, urea, and propylene glycol.

Buffers suitable for use with the invention include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, lactic acid buffers and borate buffers.

Suitable solubilizing agents include, but are not limited to, quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates.

Suitable skin penetrating agents include, but are not limited to, ethyl alcohol, isopropyl alcohol, octylphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethylsulfoxidp, fatty acid esters (eg, isopropyl myristate, methyl laurate , glycerin monooleate, and propylene glycol monooleate); and N-methylpyrrolidone.

Pharmaceutical additives

Topical formulations of the present teachings may include pharmaceutical compounds or their pharmaceutically acceptable salts, for example, but not limited to, topical corticosteroids and other anti-inflammatory agents, such as betamethasone, diplorasone, amcinonide, fluocinolone, mometasone, hydrocortisone, prednisone, and triamcinolone ; local anesthetics and analgesics, such as camphor, menthol, lidocaine, and dibucaine, and pramoxine; antifungals, such as cyclopyrox, chloroxylenol, triacetin, sulconazole, nystatin, undecylenic acid, tolnaphtate, miconizol, clotrimazole, oxiconazole, griseofulvin, econazole, ketoconozole, and amphotericin B; antibiotics and anti-infectives, such as mupirocin, erythromycin, clindamycin, gentamicin, polymyxin, bacitracin, and silver sulfadiazine; and antiseptics, such as iodine, povidin iodine, benzalkonium chloride, benzoic acid, chlorhexidine, nitrofurazine, benzoyl peroxide, hydrogen peroxide, hexachlorophen, phenol, resorcinol, and cetylpyridinium chloride.

Dosage

Dosages and dosage frequency can be determined by an experienced technician such as a trained medical professional. The dosage may depend on the activity of an a2 adrenergic receptor agonist, the characteristics of the particular topical formulation, and the identity and severity of the dermatological disorder treated or to be prevented.

In general, a compound of the invention may be present in a formulation in an amount of approximately

0.01% w / w to about 5% w / w, preferably, from about 0.05 percent to about 1 percent, more preferably, from about 0.1 percent to about 0.2 percent of the total formulation weight.

Topical Adminsitration

Generally the amount of a topical formulation applied to an area of the affected skin is in the range of about 0.1 g / cm2 to about 5 g / cm2 of the surface area of the skin, from about 0.2 g / cm2 to about 0.5 g / cm2 of the surface area of the skin.

To promote skin tightening, the topical formulations of the invention are applied topically directly to the skin in an affected area in any conventional manner well known in the art. As used herein, "improving wrinkles, folds or sagging skin" and "promoting skin tightening" includes decreasing the severity of wrinkles, folds or sagging skin, or preventing its appearance. Decreasing the severity of wrinkles, folds or sagging skin may include complete or partial inversion of wrinkles, folds or sagging skin.

In several aspects, a composition of the present teachings can be applied topically by any method known in the art, for example, with the help of a dropper or applicator bar, such as a mist by an aerosol applicator, by an intradermal patch or transdermal, or simply extending a formulation of the invention over the affected area with the fingers. Typically, an application of a topical composition can improve markedly.

20 wrinkles, folds or sagging skin in minutes after application. The results differ from one patient to another. The effects are preferably observed within approximately eight minutes, even more preferably within approximately five minutes, most preferably within approximately two minutes, and optimally immediately after the application of topical administration.

A composition can be most effective about 30 minutes after application, and the relief effects can last up to about 8 hours, up to about 12 hours, up to about 18 hours, or up to about 24 hours. Consequently, in some aspects, a composition can be applied topically to the skin at a place of wrinkles, folds or sagging skin once a day, twice a day, or three times a day.

Use of the topical formulations of the invention in combination with other treatments for skin disorders

The formulations of the invention can be used in combination with other treatments and medicaments to provide a more effective treatment or prevention of wrinkles, folds or sagging skin. In a preferred embodiment, topical formulations can be used in combination with well-known treatment regimens and medications for the

Treatment of dermatological disorders, such as those described in THE MERCK MANUAL 811-830 (Keryn A. G. Lane and other eds. 17th ed. 2001), incorporated herein by reference.

In some aspects, a formulation, composition or compound may be used in combination with another medication or treatment. In some configurations, a combination may be administered to a subject in a sequence and within a

40 time interval so that they can act together to treat or prevent wrinkles, folds or sagging skin.

Any suitable route of administration can be used to provide the additional treatment or medication that includes, but is not limited to, oral, intraoral, rectal, parenteral, topical, epicutanea, transdermal, subcutaneous, intramuscular, intranasal, sublingual, buccal, intradural, intraocular, intra-respiratory, or nasal inhalation.

In one embodiment, topical formulations can be used in combination with systemic antibiotic administration.

or retinoids that include, but are not limited to, orally dosed antibiotics, such as tetracycline, minocin, minocycline, erythromycin, and doxycycline, and orally dosed retinoids such as isotretinoins (eg, Accutane or Roaccutance).

In other embodiments, the topical formulations described herein may be used in combination with other topical treatments that include, but are not limited to, topical formulations consisting of metronidazole, hydrogen peroxide, benzoyl peroxide, lipoic acid, and azelaic acid, and sulfur preparations; Topically dosed antibiotics, such as metronidazole, clindamycin, and erythromycin; topical retinoids such as tretinoin, adapalene, tazarotene;

55 or topical steroids.

In other embodiments, the topical formulations described herein may be used in combination with other therapies such as, for example, mixed pulsed light therapy (photoderma), pulsed dye laser treatment, or electrosurgery.

Manufacturing item

Certain aspects of the present teachings include an article of manufacture comprising a topical formulation in a suitable container with label and instructions for use. The container can be, in a non-limiting example, a dropper or tube with a suitable small orifice size, such as an extended tip tube made of any

5 pharmaceutically suitable material.

A topical formulation can be filled or packed in a plastic bottle or tube. Suitable container-closure systems for packing the topical formulations of the invention are commercially available, for example, from Wheaton Plastic Products, 1101 Wheaton Avenue, Millville, N.J. 08332

10 In some configurations, a formulation may be packaged with written material, such as, for example, instructions, a booklet or a label on the package. The instructions on the label explain how to administer the topical formulations of the invention, in an amount and for a period of time sufficient to treat or prevent wrinkles, folds or sagging skin. Label instructions can be an important aspect since before a composition can be

15 approved for any particular use, this may require approval to be marketed by the United States Food and Drug Administration. Part of this process includes providing a label that will accompany the pharmaceutical composition that is ultimately sold. Accordingly, a label may include dosage and administration instructions, topical formulation composition, clinical pharmacology, drug resistance, pharmacokinetics, absorption, bioavailability, and contraindications.

EXAMPLES

The following examples are provided for illustrative purposes only and should not be construed in any way as limiting the scope of the invention. The description of an article, a composition, or a method in an example does not

25 implies that the described article or composition has been produced or not, or that the described method has been carried out or not, regardless of the tense of the verb.

Example 1

Synthesis of (5-Bromo-quinoxalin-6-yl) - (4,5-dihydro-1H-imidazol-2-yl) -amine

To a stirred solution of 6-amino-5-bromoquinoxaline hydrobromide (10 g) in distilled water (150 ml) is added thiophosgene (3 ml). The solution is stirred for two hours at room temperature and the resulting precipitate is collected by filtration, washed with water, and dried to provide 5-bromo-6-isothiocyanate-quinoxaline.

35 5-Bromo-6-isothiocyanate-quinoxaline (3.5 g.) Is dissolved directly in benzene (400 ml) and added dropwise to a well-stirred solution of ethylene diamine (15 g.) In benzene (50 ml. ). Over a period of approximately two hours, an oil separates as a bottom layer. The upper layer of benzene is poured and the oil is washed with diethyl ether and then dissolved in methanol (500 ml). The methanolic solution is refluxed until the

40 evolution of hydrogen sulfide. The methanolic solution is concentrated in vacuo to a volume of approximately 100 ml after which a yellow solid precipitates. The precipitate is collected by filtration and recrystallized from methanol to provide (5-Bromo-quinoxalin-6-yl) - (4,5-dihydro-1H-imidazol-2-yl) -amine: m.p. 250251 C.

45 Example 2

A topical aqueous solution formulation of the invention comprises (5-Bromo-quinoxalin-6-yl) - (4,5-dihydro-1H-imidazol-2-yl) -amine-L-tartrate (brimonidine tartrate) (0.15% p / p); Puriteg (0.005% w / w) (stabilized chlorine dioxide) as a preservative; and inactive ingredients: boric acid; calcium chloride; magnesium chloride; potassium chloride; purified water;

50 sodium borate; sodium carboxymethylcellulose; sodium chloride; with hydrochloric acid and / or sodium hydroxide to adjust the pH to 5.6 to 6.6. The osmolarity is in the range of 250-350 mOsmol / kg.

Example 3

A topical formulation in aqueous solution comprises (5-Bromo-quinoxalin-6-yl) - (4,5-dihydro-1H-imidazol-2-yl) -amine-Ltartrate, (brimonidine tartrate) (0.15% w / p); benzalkonium chloride (0.005% p) as a preservative; and inactive ingredients: boric acid; calcium chloride; magnesium chloride; potassium chloride; purified water; sodium borate; sodium carboxymethylcellulose; sodium chloride; with hydrochloric acid and / or sodium hydroxide to adjust the pH to 5.6 to 6.6. The osmolarity is in the range of 250-350 mOsmol / kg.

EXAMPLE 4

A topical cream formulation is described in the Table below. TABLE 2

Topical cream formulation (hydrophilic ointment)

Ingredient

 Weight percent

Brimonidine Tartrate

0.15%

Stearic acid

7%

Stearyl alcohol

5% Cetyl Alcohol

2% glycerin

10%

Sodium lauryl sulfate

one%

Propylparaben

 0.05%

Methylparaben

 0.25%

Disodium edetate

0.055

Distilled water

csp

To prepare the formulation, stearyl alcohol and white petrolatum were melted in a steam bath, and heated to approximately 75 degrees C. The other ingredients, previously dissolved in water and heated to 75 degrees C, were then added, and The mixture was stirred until frozen. The mixture was then allowed to cool with stirring, and added

10 after brimonidine tartrate as a concentrated solution.

Example 5

A topical ointment formulation is described in the Table below.

TABLE 3

Ointment formulation (hydrophilic ointment)

Ingredients

Weight

Brimonidine Tartrate

10 g

Cholesterol

 30 g

Stearyl alcohol

30 g

White wax

80 g

White petrolatum

850 g

To prepare the formulation, stearyl alcohol and white wax were mixed together in a steam bath. The cholesterol was then added and stirred until completely dissolved. The white petrolatum was added afterwards and mixed. The mixture was removed from the bath and stirred until frozen. With continuous stirring, brimonidine tartrate was added as a concentrated slurry.

Example 6

A gel formulation is described in the Table below.

TABLE 4

Gel formulation

Ingredients

 Weight %

Brimonidine Tartrate

1.0%

Gel formulation

Ingredients

Weight %

Methylparaben NF

0.15%

NF propylparaben

0.03%

NF hydroxyethyl cellulose

1.25%

USP disodium edetate

0.05%

Purified water, USP

100% csp

Example 7 A gel formulation is described in the Table below. TABLE 5

Gel formulation

Ingredients

 Weight %

Brimonidine Tartrate

1.0%

Methylparaben

0.20%

Propylparaben

 0.05%

Carbomer 934P NF

1.0%

Sodium hydroxide

csp pH 7

Purified water

100% csp

The ingredients are mixed together and aqueous sodium hydroxide is slowly added to the mixture until a pH of about 7 is reached and the gel is formed.

Example 8 A gel formulation is described in the Table below. 15 TABLE 6

Gel formulation

Ingredients

 Weight %

Brimonidine Tartrate

1.0%

Methylparaben

 0.2%

Propylparaben

 0.05%

"CARBOPOL ®"

1.0%

Triethanolamine

qs pH 7

Water

 100% csp

The ingredients are mixed together and stirred. Triethanolamine is added until a pH of approximately 7 is achieved. Example 9 A foam formulation is described in Table 7 below.

TABLE 7

Foam formulation

Ingredients

Amount (% by weight)

Brimonidine Tartrate

0.2

Stearic acid

4.2

Lauret-23

 1.4

Sodium lauryl sulfate

0.5

Triethanolamine

2.2

Butylated Hydroxytoluene (BHT)

0.01

Fragrance

0.5

Propeller Aeron A-31

3

Water

87.99

Water is heated to 80-85 ° C, after which stearic acid is added. Once the stearic acid melts,

Lauret-23 is added, melted, and mixed well. Then, triethanolamine is added and the resulting composition is

5 Mix well for about 30 minutes to form a soap. The resulting soap is then cooled to

approximately 65 ° C, after which sodium lauryl sulfate is added. Then the composition mixes well. TO

Then, BHT and brimonidine tartrate are added, followed by mixing. The resulting composition is cooled

then and the fragrance is added. The product is packed with the Aeron A-31 propellant in an aerosol can using

Conventional techniques and stirred mechanically for 5 minutes. The product is dispensed as a cone-shaped spray that is deposited on the skin as a layer of rich soapy foam that quickly covers a wide area of

skin.

Examples 10-13

15 Additional foam formulations are described in Table 8 below.

TABLE 8

Foam formulations

Ingredients

 Amount (% by weight)

Example 10 Example 11 Example 12 Example 13

Brimonidine Tartrate

0.1 0.15 0.2 0.25

Stearic acid

6.3  5.0  3.6  3.1

Lauret-23

2.1 1.7 1.2 1.0

Sodium lauryl sulfate

0.8  0.6  0.5  0.4

Triethanolamine

3.2  2.6  1.9  1.6

Butylated Hydroxytoluene (BHT)

0.02 0.02 0.01 0.01

Fragrance

0.5  0.5  0.5  0.5

Propeller Aeron A-31

3 3 3 3

Water

83.98  86.43  89.09  90.14

Preparation: these foam formulations are prepared and packed as in Example 9. The product is dispensed as a cone-shaped spray that is deposited on the skin as a layer of rich soapy foam that quickly covers a wide area of skin.

Example 14 An additional foam formulation is described in Table 9 below. TABLE 9

Foam formulation

Ingredient

Amount (% by weight)

Brimonidine Tartrate

0.2

Water

 91.11

Palmitic acid

2.12

Lauret-23

 0.93

Triethanolamine (99%)

1.13

Cetyl dimethicone copolyol

0.19

Mineral oil

0.31

Stearyl alcohol

0.31

Lauramida DEA

0.15

PEG-150 distearate

0.05

Imidazolidinylurea

0.0016

Methylparaben

 0.0005

Propylparaben

 0.00003

Frozen Dry Aloe Powder

0.0015

Fragrance

0.50

Propeller Aeron A-31

3.00

5 The aqueous phase is prepared as follows. The water is heated to 80 ° C., after which palmitic acid is added. Once the palmitic acid melts, laureth-23 is added, melted, and mixed well. Then, triethanolamine is added and the resulting composition is mixed well for about 15 minutes to form a soap.

Stearyl alcohol, mineral oil, DEA lauramide, cetyl dimethicone copolyol, PEG-150 distearate, and BHT are mixed and mixed.

10 heat at 55 ° C to form the oil phase. The oil is combined with the aqueous phase at 80 ° C. and mixed well for approximately 15 minutes. The resulting mixture is then cooled to room temperature and the imidazolidinyl urea, methylparaben, and propylparaben are added, and then mixed well. Then the brimonidine tartrate is added and mixed well. Next, the fragrance is added, followed by careful mixing. The aloe is then dissolved in reconstituted water and added with slow mixing to form the product formulation that is then packed in a

15 aerosol can as described in Example 9.

The product is dispensed as a cone-shaped spray that is deposited on the skin like a layer of rich soapy foam that quickly covers a wide area of skin.

20 Example 15

An additional, non-soapy foam formulation is described in Table 10 below.

TABLE 10

Foam formulation

Ingredient

Amount (% by weight)

Brimonidine Tartrate

0.2

Ethanol

 6

PVM / MA ethyl ester

4

Foam formulation

Ingredient

Amount (% by weight)

Copolyol dimethicone copolymer

0.1

Water

 80.37

PVP / VA copolymer

one

Sodium lauryl sulfate

one

Oleth-20

 0.5

MEA cocamida

0.05

Methylparaben

 0.1

Aminomethyl Propanol

0.53

Stearalkonium Chloride

0.05

Esteareth-16

0.1

Panthenol

0.5

Fragrance

0.5

Aeron A-46

5

The alcohol phase is prepared by dissolving ethyl ester of the PVM / MA copolymer in ethanol, after which dimethicone is added and mixed well. The aqueous phase is prepared by heating the water to 65 ° C, after which the PVP / VA copolymer is added and mixed well. The oil phase is prepared by mixing oleth-20, cocamide MEA, and esteareth-16 a

5 60 ° C to form a mixture. The oil phase is then added to the aqueous phase at 65 ° C and mixed well. Next, the methylparaben is added to the mixture, followed by mixing, after which aminomethyl propanol, stearalkonium chloride, and panthenol are added and mixed until uniform. The resulting composition is cooled to room temperature, after which the alcohol phase is added and mixed well. The fragrance is then added and carefully mixed to form the product. The product is then packed in an aerosol can.

10 The product is dispensed as a cone-shaped spray that is deposited on the skin like a layer of rich soapy foam that quickly covers a wide area of skin.

Example 16

Use of Oxymetazoline

An oxymetazoline solution (Afrin®, 0.05% solution, Schering-Plow HealthCare Products) is placed in a cotton tip swab and applied to approximately 4 cm2 of the naso-facial skin that shows wrinkles, folds or sagging skin. 20 the skin.

Example 17

Epinephrine use

25 An epinephrine solution (Epipen®, trademark of Dey®, L.P.) containing approximately 0.3 mg of epinephrine is placed in a glass container. The solution is placed on a cotton tip swab and then applied to approximately 4 cm2 of the naso-facial skin showing wrinkles, folds or sagging skin.

30 Example 18

A middle-aged woman has severe wrinkles on her face. She applies 0.2% COL-118 (an a2 adrenergic receptor agonist supplied by CollaGenex Pharmaceuticals, Inc., Newtown, PA). Wrinkles decrease markedly at 5 minutes by casual observation. After about 10 minutes, almost all wrinkles are gone. He

35 effect lasts at least 8 hr.

Definitions

As used herein, the term "prodrug" refers to a precursor of the drug that is inactive but can be activated by a biological or biochemical process, such as, for example, enzymatic hydrolysis.

The phrase "pharmaceutically acceptable salt (s)", as used herein, means those salts of the compounds of the invention that are safe and effective for topical use in mammals and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the compounds of the present teachings. Pharmaceutically acceptable acid addition salts include, but are not limited to, salts of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate , succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, sucrate, format, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, ptoluenesulfonate and pamoate (i.e. 1,1'-methylene-bis- (2-hydroxy-3- naphthoate)). Certain compounds described herein may form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. For a study of pharmaceutically acceptable salts see BERGE et al., 66 J. PHARM. Sci. 1-19 (1977), incorporated herein by reference.

The term "pharmaceutically acceptable topical formulation" as used herein means any formulation that is pharmaceutically acceptable for topical administration of a compound. A "topical formulation" may comprise at least one compound of the present description. The selection of the topical formulation will depend on several factors, including the nature of the symptoms to be treated or prevented, the physicochemical characteristics of the particular compound of the invention and other excipients present, its stability in the formulation, available manufacturing facility, and cost limitations

As used herein, a "therapeutically effective amount" of a compound means the amount of the compound that is effective in treating or preventing wrinkles, folds or sagging skin.

As used herein, the term "subject" means any animal, preferably a mammal, to which the compounds or topical formulations of the present teachings have been administered or will be administered. The term "mammal" as used herein, encompasses any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans etc.

The term "analog" refers to a chemical compound that is structurally similar to a compound of origin and has chemical properties or pharmaceutical activity in common with the compound of origin. The analogs include, but are not limited to, homologs, that is, when the analogs differ from the compound of origin in one or more carbon atoms in series; position isomers; compounds that differ by exchanging one or more atoms for a different atom, for example, replacing a carbon atom with an oxygen, sulfur, or nitrogen atom; and compounds that differ in the identity of one or more functional groups, for example, the compound of origin differs from its analog by the presence

or absence of one or more suitable substituents. Suitable substituents include, but are not limited to, (C1C8) alkyl; (C1-C8) alkenyl; (C1-C8) alkynyl: aryl; (C2-C5) heteroaryl; (C1-C6) heterocycloalkyl; (C3-C7) cycloalkyl; O - (C1C8) alkyl; O - (C1-C8) alkenyl; O - (C1-C8) alkynyl; O-aryl; CN; OH; oxo; halo, C (O) OH; COhalo; O (CO) halo; CF3, N3; NO2, NH2; NH ((C1-C8) alkyl); N ((C1-C8) alkyl) 2; NH (aryl); N (aryl) 2 N ((C1-C8) alkyl) (aryl); (CO) NH2; (CO) NH ((C1-C8) alkyl); (CO) N ((C1C8) alkyl) 2; (CO) NH (aryl); (CO) N (aryl) 2; O (CO) NH2; NHOH; NOH ((C1-C8) alkyl); NOH (aril); O (CO) NH ((C1-C8) alkyl); O (CO) N ((C1-C8) alkyl-) 2; O (CO) NH (aryl); O (CO) N (aryl) 2; CHO; CO ((C1-C8) alkyl-); CO (aryl); C (O) O ((C1-C8) alkyl); C (O) O (aryl); O (CO) ((C1-C8) alkyl); O (CO) (aryl); O (CO) O ((C1-C8) alkyl-); O (CO) O (aryl); S - (C1-C8) alkyl; S - (C1-C8) alkenyl; S - (C1-C8) alkynyl; S-aryl; S (O) C1-C8) alkyl; S (O) - (C1-C8) alkenyl; S (O) - (C1-C8) alkynyl; and S (O) -aryl; S (O) 2- (C1C8) alkyl; S (O) 2 - (C1-C.sub- .8) alkenyl; S (O) 2 - (C1-C8) alkynyl; and S (O) 2-aryl. A person skilled in the art can easily choose a suitable substituent based on the stability and pharmacological activity of a compound.

The term "alkyl" means a saturated, monovalent, branched or unbranched hydrocarbon chain. Examples of alkyl groups include, but are not limited to, (C1-C3) alkyl groups, such as methyl, ethyl, propyl, isopropyl and (C4-C8) alkyl groups, such as 2-methyl-1-propyl, 2- methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1propyl, 2-methyl-pentyl, 3-methyl-1- pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1- butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl, heptyl, and octyl. An alkyl group may be unsubstituted or substituted with one or two suitable substituents.

The term "alkenyl" means a monovalent, branched or unbranched hydrocarbon chain having one or more double bonds therein. The double bond of an alkenyl group may be unconjugated or conjugated with another unsaturated group. Suitable alkenyl groups include, but are not limited to (C2-C8) alkenyl groups, such as vinyl, allyl,

butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4- (2-methyl-3-butene) pentenyl. An alkenyl group may be unsubstituted or substituted with one or two suitable substituents.

The term "alkynyl" means a monovalent, branched or unbranched hydrocarbon chain having one or more triple bonds therein. The triple bond of an alkynyl group may be unconjugated or conjugated with another unsaturated group. Suitable alkynyl groups include, but are not limited to, (C2-C8) alkynyl groups, such as ethynyl, propynyl, butynyl, pentinyl, hexinyl, methylpropyl, 4-methyl-1-butynyl, 4-propyl-2-pentinyl-, and 4-butyl-2-hexinyl. An alkynyl group may be unsubstituted or substituted with one or two suitable substituents.

The term "aryl" means a monocyclic or polycyclic-aromatic group comprising carbon and hydrogen atoms. Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic portions such as 5,6,7,8-tetrahydronaphthyl. An aryl group may be unsubstituted or substituted with one or two suitable substituents. Preferably, the aryl group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as "(C6) aryl".

The term "heteroaryl" means an aromatic monocyclic or polycyclic ring comprising carbon atoms, hydrogen atoms, and one or more heteroatoms, preferably 1 to 3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur. As is well known to those skilled in the art, heteroaryl rings have less aromatic character than their all-carbon counterparts. Thus, for the purposes of the invention, a heteroaryl group only needs to have some degree of aromatic character. Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,) - and (1,2,4) -triazolyl, pyrazinyl , pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, phenyl, isoxazolyl, and oxazolyl. A heteroaryl group may be unsubstituted or substituted with one or two suitable substituents. Preferably, a heteroaryl group is a monocyclic ring, wherein the ring comprises 2 to 5 carbon atoms and 1 to 3 heteroatoms, referred to herein as "(C2-C5) heteroaryl".

The term "cycloalkyl" means a non-aromatic, monocyclic or polycyclic ring comprising carbon and hydrogen atoms. A cycloalkyl group may have one or more carbon-carbon double bonds in the ring as long as the ring does not become aromatic by its presence. Examples of the cycloalkyl group include, but are not limited to, (C3-C7) cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic terpene and cyclic groups and (C3-C7) cycloalkenyl, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl, and unsaturated bicyclic and cyclic terpenes. A cycloalkyl group may be unsubstituted or substituted by one or two suitable substituents. Preferably, the cycloalkyl group is a monocyclic ring or bicyclic ring.

The term "heterocycloalkyl" means a monocyclic or polycyclic non-aromatic ring comprising carbon and hydrogen atoms and at least one heteroatom, preferably, 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. A heterocycloalkyl group may have one or more carbon-carbon double bonds or carbon-heteroatom double bonds in the ring as long as the ring is not made aromatic by its presence. Examples of heterocycloalkyl groups include aziridinyl, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, and pyranyl. A heterocycloalkyl group may be unsubstituted or substituted with one or two suitable substituents. Preferably, the heterocycloalkyl group is a monocyclic or bicyclic ring, more preferably, a monocyclic ring, wherein the ring comprises 2 to 6 carbon atoms and 1 to 3 heteroatoms, referred to herein as (C1-C6) heterocycloalkyl.

The term "halogen" encompasses fluorine, chlorine, bromine, and iodine. Consequently, the term "halo" means fluoro, chloro, bromo, and iodo.

In one embodiment, "reduce" refers to an improvement, prophylaxis, or reversal of a disease or disorder, or at least one discernible symptom of it, for example, reducing wrinkles, folds or sagging skin. In another embodiment, "reduce" refers to an improvement, prophylaxis, or reversal of at least one measurable physical parameter related to wrinkles, folds or sagging skin, not necessarily discernible in or by the mammal. In yet another embodiment, "reduce" refers to inhibiting or decreasing the progress of a disease or disorder, physically, for example, stabilization of a discernible symptom, physiologically, for example, stabilization of a physical parameter, or both. In yet another embodiment, "reduce" refers to delaying the onset of a disease or disorder.

In certain embodiments, the compounds of the invention can be administered as a preventive measure. As used herein, "prevention" or "prevent" refers to a reduction in the risk of acquiring a given disease or disorder. In a preferred mode of the embodiment, the compounds of the invention are administered as a preventive measure to a subject who has a predisposition to wrinkles, folds or sagging skin despite the fact that disease symptoms are absent or minimal. .

As used herein, "carbomer" is the USP designation for various polymeric acids that are dispersible but insoluble in water. When the acid dispersion is neutralized with a base, a clear, stable gel is formed. Carbomer 934P is physiologically inert and is not a primary irritant or sensitizer. Other carbomers include 910, 940, 941, and 5 1342.

The compounds of this invention are limited to those that are chemically feasible and stable. therefore, a combination of substituents or variables in the compounds described above is permissible only if said combination results in a stable or chemically feasible compound. A stable or chemically feasible compound is

10 one in which the chemical structure is not substantially altered when it is maintained at a temperature of 40 ° C or less, in the absence of moisture or other chemically reactive conditions, for at least one week.

All stereoisomers of the compounds of the present invention are contemplated, in admixture or in pure or practically pure form. The definition of the compounds according to the invention encompasses all possible stereoisomers.

15 and mixtures thereof; This also encompasses racemic forms and isolated optical isomers that have the specified activity. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation, or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from racemates from conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.

20 A list followed by the word "comprising" is inclusive or open-ended, that is, the list may or may not include additional elements not mentioned. A list followed by the words "consisting of" is exclusive or closed-ended, that is, the list excludes any item not specified in the list.

25 All numbers in this description are approximate unless otherwise indicated.

The method of treating a condition, disorder or disease with a chemical compound or a chemical composition includes the use of chemical compounds or chemical composition in the manufacture of a medicament for the treatment of the condition, disorder or disease, that is, Swiss-style claims. . A compound or group of compounds that are effective

30 for the treatment of a condition, disorder or disease include the compound or group of compounds for use in the treatment of the condition, disorder or disease.

The person skilled in the art can make many variations and modifications to the embodiments of the invention described above.

The term "group consisting of" is equivalent to the term "group that includes".

Claims (12)

one.

A composition comprising at least one active ingredient selected from an a2 adrenergic receptor agonist, a pharmaceutically acceptable salt thereof and a combination thereof for use in the therapeutic reduction of wrinkles, folds or sagging skin, wherein the A2 adrenergic receptor agonist is selected from the group consisting of brimonidine, tetrahydrozalin, oxymetazoline, and xylometazoline, and wherein said composition is to be administered topically for sagging, folds, and / or wrinkles of the skin of a person in need Treatment in an effective amount to improve wrinkles, folds or sagging skin.

2.

A composition according to claim 1, wherein the at least one a2 adrenergic receptor agonist is a reversible a2 adrenergic receptor agonist.

3.

A composition according to claim 1, wherein the composition further comprises at least one pharmaceutically acceptable carrier.

Four.

A composition according to claim 3, wherein the composition is in a form selected from the group consisting of an atomizer, a mist, an aerosol, a lotion, a gel, a cream, an ointment, a foam, a paste, an ointment, an emulsion, a liposomal suspension, a colloid and a combination thereof.

5.

A composition according to claim 3, wherein the composition further comprises a cosmetic, a makeup base, a moisturizer and a sunblock.

6.

A composition according to claim 1, wherein the amount of composition to be applied to the affected area is in the range of about 0.1 g / cm2 to about 5 g / cm2 of the skin surface area.

7.

A composition according to claim 1, wherein the composition further comprises at least a second active ingredient selected from the group consisting of azelaic acid, benzoyl peroxide, isotretinoin, an antibiotic, a chemically modified antibiotic, a pharmaceutically acceptable salt thereof. and a combination thereof, in an amount effective to improve wrinkles, folds or sagging skin.

8.

A composition according to claim 7, wherein the antibiotic is selected from the group consisting of clindamycin, doxycycline, erythromycin, metronidazole, sulfacetamide, and tetracycline.

9.

A composition according to claim 1, wherein an amount effective to improve wrinkles, folds or sagging skin is an amount that improves wrinkles, folds or sagging skin within about 5 minutes after administration.

10.

A composition according to claim 1, wherein an amount effective to improve wrinkles, folds or sagging skin is an amount that improves wrinkles, folds or sagging skin for at least about 8 hours, preferably for up to about 12 hours, more preferably for up to about 18 hours, and most preferably for up to about 24 hours.

eleven.

Use of a composition as defined in any one of claims 1 to 10 for the preparation of a medicament for reducing wrinkles, folds or sagging skin.

12.

Use of a cosmetic product comprising at least one of an a2 adrenergic receptor agonist and / or a pharmaceutically acceptable salt thereof for the cosmetic reduction of wrinkles, folds or sagging skin, wherein the adrenergic receptor agonist a2 is it selects from the group consisting of brimonidine, tetrahydrozalin, oxymetazoline, and xylometazoline, and wherein said composition is administered topically for sagging, folds, and / or wrinkles of a person's skin.